TESTOSTERONE INCREASES HUMAN PLATELET THROMBOXANE A(2) RECEPTOR DENSITY AND AGGREGATION RESPONSES

Background The incidence of thrombotic cardiovascular disease is greater in men than in premenopausal women. Testosterone has been implicated as a significant risk factor for cardiovascular disease and for acute myocardial infarctions and strokes in young male athletes who abuse anabolic steroids. Thromboxane A(2) (TXA(2)) is a vasoconstrictor and platelet proaggregatory agent that has been implicated in the pathogenesis of cardiovascular disease. We therefore tested the hypothesis that testosterone regulates the expression of human platelet TXA(2) receptors. Methods and Results In a double-blind, placebo-controlled, randomized, parallel-group study, we determined the effects of testosterone cypionate 200 mg IM given twice, 2 weeks apart, or saline placebo in 16 healthy men. Platelet TXA(2) receptor density (B-max) and dissociation constant (K-d) were measured by use of the TXA(2) mimetic I-125-BOP. Platelet aggregation responses to I-BOP and to thrombin and plasma testosterone concentrations were measured before treatment (pretreatment phase), at 2 and 4 weeks (active phase), and again at 8 weeks (recovery phase). Treatment with testosterone was associated with an increase in the B-max value from 0.95+/-0.13 to 2.10+/-0.4 pmol/mg protein (n=9), with a peak effect at 4 weeks (P=.001), returning to baseline by 8 weeks. There was no significant change in B-max values in the saline-treated group. The K-d values were unchanged. Testosterone treatment was associated with a significant increase in the maximum platelet aggregation response to I-BOP (P<.001) at 4 weeks and returned to baseline at 8 weeks. The EC(50) values were not significantly changed. Platelet TXA(2) receptor density was positively correlated (r=.56, P<.001, n=32 measurements) with pretreatment (endogenous) plasma testosterone levels (range, 215 to 883 ng/dL) but not K-d. Conclusions Testosterone regulates the expression of platelet TXA(2) receptors in humans. This may contribute to the thrombogenicity of androgenic steroids.